Elsevier

Brain Research Reviews

Volume 20, Issue 2, February 1995, Pages 250-267
Brain Research Reviews

The N-methyl-d-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias

https://doi.org/10.1016/0165-0173(94)00014-GGet rights and content

Abstract

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-d-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDa antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependant. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez-like circuit.

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      Acute administration of PCP and other antagonists of the NMDA-type glutamate receptor has been reported to produce necrotic vacuolization of neurons associated with increases in HSP70 and glial fibrillary acidic protein (GFAP) in the retrosplenial/posterior cingulate cortex, as well as in certain corticolimbic regions (Fix et al., 1993; Olney et al., 1989; Sharp et al., 1992). Long-term/repeated PCP administration leads to persistent schizophrenia symptoms including, among others, impairment in thinking, inability to distinguish reality from fantasy, and a loss of emotion or flattened affect (Ellison, 1995). Atrophy in the prefrontal and cingulate cortices, and hippocampal areas of the brain as demonstrated by neuroimaging studies, may underlie the behavioral deficits observed in PCP addicts (Micallef et al., 2003; Wang et al., 2004).

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